The invention relates to methods for obtaining compounds useful in perfumery, particularly to methods for obtaining ketones such as that having formula 1a,b (3xcex1-acetyl-2,3,4xcex1,4axcex2,5,6,7,8-octahydro-3xcex2,4xcex2,5,5-tetramethylnaphthalene) in its racemic or optically active form: 
For simplicity, only one enantiomer will be shown for ketone 1 and its precursors in the following text and schemes of this Application, although the invention may relate to either enantiomeric mixtures or optically pure materials.
Ketones according to Formula 1 are recognized in the art.
For example, G. Frxc3xa1ter et al. (Tetrahedron, 1998, Vol. 54, pp. 7633-7703, especially pp. 7651-7653) and C. Nussbaumer et al. (Helvetica Chimica Acta, 1999, Vol. 82, pp.1016-1024) discuss ketone 1 as an impurity in a commercial product Iso E Super(copyright), which is obtained by an acid catalyzed cyclization of ketone 2 (Scheme 1) and which contains mainly ketone 3.
Despite its small concentration in Iso E Super(copyright), ketone 1 is apparently responsible for the intense amber-woody odor of the whole product. This is because ketone 1 has an extremely low odor threshold of about 5 pg/L. The formation of ketone 1 during the cyclization of 2 can be explained via partial isomerization of starting material 2 into ketone 4 followed by the cyclization of the latter. However, the small concentration of ketone 1 in the product is believed to be due to a higher rate of the cyclization of 2 into 3 compared to the rate of its isomerization into 4. 
Copending U.S. patent application Ser. No. 09/136,488 (M. Erman et al., Millennium Specialty Chemicals, Inc.) shows that the concentration of ketone 1 in the product of cyclization of 2 can be increased when the reaction is carried out in the presence of hydroxyl-containing compounds. While the positive effect on yield by way of this process is significant, the concentration of ketone 1 remains less than about 10%.
Alternatively, a sophisticated multi-step synthesis of ketone 1 from xcex1-ionone according to the Scheme 4 below was disclosed in EP 464357, U.S. Pat. Nos. 5,180,709, and 5,214,160 (F. Etzweller et al., Givaudan-Roure S.A.), and also in: C. Nussbaumer et al. (Helv.Chim. Acta, 1999, Vol. 82, pp.1016-1024). The method comprises a cuprate methylation of xcex1-ionone into ketone 10, haloform oxidation to acid 11, conversion into ester 12, hypochlorite oxidation to allylic chloride 13, ozonolysis and subsequent Zn reduction to ketone 14, addition of acetylene followed by partial hydrogenation of the resulting lactone 15, methylation and silylation of lactone 16 to give enol silyl ether 17, its thermal rearrangement into ketone 18, and finally methylation with MeLi providing ketone 1. Multiplication of yields given in Scheme 4 shows that the total yield of ketone 1 based on xcex1-ionone is below 8% of the theory. 
Furthermore, the complexity of this synthesis severely limits its commercial applicability.
Thus, there are basically two known techniques for the preparation of ketone 1:
1) A multi-step synthesis from (xcex1-ionone; and
2) A one-step synthesis from ketone 2, which provides isomeric mixtures containing ketone 1.
Both techniques, however, provide a yield of ketone 1 that is typically less than 10%. Unfortunately, isolation of ketone 1 from mixtures containing less than 10% ketone 1 concentration is a laborious and a low-yield process. Thus, the need still exists for an improved process for making ketone 1.
The present invention is based, at least in part, on the surprising discovery that contacting a ketone 2 with certain catalytic materials can cause its isomerization into ketone 4, thus providing, in high yield, intermediate mixtures containing ketone 4 and unreacted ketone 2, together with smaller amounts of other ketones, e.g., ketones 19 and 20 with a terminal double bond, and also smaller amounts of other cyclization products, ketones 1, 3, 7, 8, 9. Moreover, it has been discovered that the desirable isomerization of ketone 2 into ketones 4 and 19 can be significantly faster than the cyclization of ketone 2 into ketones 3, 7, and 8, and also faster than the secondary cyclization of 4 into 1 and 9. After a separate step of the cyclization of the intermediate mixture, a significant improvement in the yields of ketone 1 can be obtained.
In one aspect, the present invention relates to a process for obtaining ketone 1 that includes the steps of:
a. isomerization of ketone 2 into a mixture of isomeric ketones including ketone 4;
b. cyclization of the mixture of isomeric ketones into a mixture containing ketone 1, where the amount of ketone 1 is increased as compared to existing techniques. The process can further include an optional purification of ketone 1.
Each of steps a and b preferably employ a catalyst, and the catalyst for step a differs from that of step b.
The present invention will be discussed in greater detail below.
One embodiment of the invention process is schematically illustrated below. 
Thus, in one preferred embodiment, the invention provides a process for obtaining ketone of formula 1a,b in its racemic or optically active form, comprising:
a. contacting a ketone represented by formula 2a,b in its optically active or racemic form with an isomerization catalyst under conditions and for a time sufficient to obtain an intermediate mixture, which intermediate mixture contains a ketone represented by formula 4a,b in its optically active or racemic form; and
b. subsequently contacting the intermediate mixture, or a fraction thereof, with an acid catalyst. 
xe2x80x9cKetone of formula 1a,b in its racemic or optically active form,xe2x80x9d refers to ketone of formula 1a, ketone of formula 1b, or a mixture of ketones 1a and 1b in a racemic or optically active ratio. The ketone 2a,b is preferably present in a starting material also containing its structural isomers. To this end, the ketone 2a,b is preferably the main component in the starting material and is preferably present in an amount of about 70% to about 99% by weight of the starting material.
The process of the present invention allows for the production of significant amounts of ketone 4a,b. By xe2x80x9csignificantxe2x80x9d it is meant an amount greater than a trace or impurity level of the component.
The molar conversion of ketone 2a,b to ketone 4a,b in step (a) is preferably greater than about 5%, more preferably 11%, and even more preferably greater than about 20%, specifically about 20% to about 30%. The intermediate mixture further contains unreacted ketone 2, preferably present in an amount greater than 20%, more preferably greater than 30% specifically about 30% to about 60%. The intermediate mixture may further comprise ketones with a terminal double bond, such as those represented by formulas 20a,b and/or 19a,b. 
Accordingly, in one particularly preferred embodiment, the ketone 4a,b is one of three major constituents of the intermediate mixture.
The term xe2x80x9cmainlyxe2x80x9d refers to a composition in which the xe2x80x9cmainxe2x80x9d constituent is present in a larger proportion than the other constituent(s).
The term xe2x80x9cmajorxe2x80x9d similarly refers to components that are greater in proportion to the overall mixture than any other components. Thus, if a component is one of three major components, the component is the first, second, or third highest concentration component of all components in the composition.
This step employs a catalyst suitable for forming ketone 4a,b, which catalyst is preferably an isomerization catalyst. The isomerization catalysts can include any catalysts recognized in the art that are suitable for catalyzing an isomerization reaction. Examples of suitable materials include various classes and groups of compounds such as salts, oxides, hydroxides, acids, heteropolyacids, complexes, metals, metal hydrides, amides, metal-graphite intercalation compounds, transition metals on carriers, clays, sorbents, zeolites, molecular sieves, etc. It must be understood that this list of catalysts is only exemplary, and is not restrictive to the invention.
Preferably, the catalysts are solid under normal conditions. However, when the isomerization reaction temperature exceeds the catalyst""s melting point, the catalyst is used in its molten state.
The preferred catalysts include inorganic salts such as hydrosulfates, pyrosulfates, hydrophosphates, perchlorates and similar salts, for example KHSO4, NaHSO4, LiHSO4, K2S2O7, KH2PO4, NaH2PO4, K2HPO4, Na2HPO4, LiClO4, NaHF2, etc.
The more preferred catalysts include hydrosulfates KHSO4 and NaHSO4. To the best of our knowledge, this is the first application of these hydrosulfates for the catalysis of the double bond migration; see for example R. Larock. Comprehensive Organic Transformations. VCH Publishers, Inc. 1989, Section xe2x80x9cIsomerization of alkenesxe2x80x9d (pp. 110-114).
The catalysts can be used in either anhydrous, or fused form or hydrated form, for example NaHSO4.H2O. The catalysts can be mixtures of two or more catalysts, or mixtures of active catalysts with catalytically inactive materials, or mixtures of the active catalysts with materials possessing lower catalytic activity.
Alternatively, the catalyst for use in the invention can be prepared by applying a catalytically active material onto the surface or into the volume of an inactive or less active material or sorbent, which is preferably solid at room temperatures. Still another alternative involves impregnating an inactive or less active material with a solution of a catalyst, with following optional removal of the solvent, which is usually water. An example of such modification is the KHSO4/alumina catalyst.
Typically, the most preferred isomerization catalysts are those which provide for maximum isomerization of ketone 2 into ketones 4 and 19 and minimum cyclization of ketones 2, 19, and 4 into ketones 1, 3, 7, 8. Formation of significant amounts of ketone 1 during isomerization is rather undesirable because of its tendency to the secondary isomerization into 9.
A temperature range for the isomerization reaction is between about 0xc2x0 C. and about 550xc2x0 C. A preferred temperature range is between about 120xc2x0 C. and about 300xc2x0 C. The reaction can be carried out in the presence or in the absence of an organic solvent. Examples of suitable solvents include high boiling hydrocarbons such as heptadecane, high boiling point alcohols such as cetyl alcohol, glycols and the like.
The isomerization can be implemented in either batch or continuous format. It can be carried out under atmospheric pressure, under reduced pressure, or under increased pressure. For example, where the reaction is performed under conditions of continuous removal of ketone 4 by techniques such as fractional distillation, reduced pressures can be used. Alternatively, where the temperature is significantly higher than the boiling point of the ketones 2 and 4, the process can be performed in a sealed environment or under increased pressures.
During the reaction, starting ketone 2 can be in the liquid phase or in the vapor phase, or distributed between liquid and vapor phases. Ketone 4 boils at slightly lower temperature than ketone 2, therefore ketone 4, or a product enriched in ketone 4, can be continuously removed from the reaction mixture by fractional distillation.
A preferred weight ratio of ketone 2 to the catalyst in a batch process is between 0.1 to 500, and a more preferred weight ratio of ketone 2 to the catalyst is from about 0.5 to about 5. For continuous isomerization reactions, the weight ratio of ketone 2 to the catalyst is not limited.
Subsequent to isomerization, the isomerization product is subjected to the cyclization reaction. Quite surprisingly, in the cyclization of the isomerization product according to the invention, ketone 1 can be present in an improved yield, preferably, about 11% or higher, more preferably about 16% and higher. Thus, the ketone 1 can be considered a major product as opposed to a xe2x80x9cminor impurity.xe2x80x9d
Under preferred conditions, the resulting concentration of ketone 1 can even exceed the concentration of any other cyclization product (ketones 3, 7, 8, 9); see, e.g., Example 7. This is even more surprising because it means that the cyclization of ketone 4 into ketone 1 (xcex3-isomer) is faster than the cyclization of 4 into ketone 9 (thermodynamically preferred xcex2-isomer), faster than cyclization of 2 into 3, and also faster than the secondary isomerization of ketone 1 into 9 and other secondary isomerizations.
The cyclization process can be carried out over a wide variety of reaction conditions and in the presence or in the absence of organic solvents, in the presence or in the absence of hydroxyl-containing additives. Examples of solvents include high boiling hydrocarbons such as heptadecane, high boiling point alcohols such as cetyl alcohol, glycols and the like with examples of additive including alcohols and carboxylic acids such as those described in copending U.S. patent application Ser. No. 09/136,488, which is incorporated by reference in its entirety.
The cyclization can be performed either continuously or batch-wise. A preferred temperature range for the cyclization is from about 0xc2x0 C. to about +150xc2x0 C. Moreover, this step is preferably performed in the presence of cyclization catalyst. In this regard, acid catalysts are preferred.
The process of the cyclization can be carried out with a great variety of acid catalysts or mixtures of acid catalysts, including any catalyst known in the art for cyclizing 1,5-dienes. The acid catalyst for the cyclization can be any Lewis or Brxc3x6nsted acid. Typically, the acid catalyst is a Brxc3x6nsted acid, a mixture of Brxc3x6nsted acids, or a solution of one or more Brxc3x6nsted acids in water. Preferred Brxc3x6nsted acids are either organic or inorganic and include phosphoric, sulfuric, formic, p-toluenesulfonic, and sulfosalicylic acids. Most preferred acid catalysts are phosphoric, sulfuric, and formic acids, and their solutions in water.
The cyclization is carried out with a preferred weight ratio of the intermediate isomeric mixture to the acid catalyst from about 0.1 to about 100. A more preferred weight ratio of the isomeric mixture to the acid catalyst is from about 0.5 to about 10.
When the cyclization is carried out in the presence of aqueous acids, formation of some small amounts of by-product hydroxyketones 21 and 22 may be observed (Scheme 6), which can be readily separated from the main product by distillation. 
The higher boiling fraction containing hydroxyketones 21 and 22 can be cyclized separately to give additional quantities of the cyclization product having a similar isomeric composition, usually with slightly lower levels of ketone 1.
After the cyclization step, a product containing ketone 1, preferably as one of the major components or as the major component, can be used as a fragrance or a component of a fragrance without additional purification. Alternatively, ketone 1 can be isolated and purified by conventional means, such as:
fractional distillation;
crystallization of impurities at reduced temperature;
oximation with hydroxylamine followed by crystallization and recrystallization of the oxime, then followed by regeneration from the oxime; or
any combination of these methods.
After the cyclization, separation of the catalyst from the isomerization product is not necessary, but is preferred, especially in the case when it is desirable to reuse the catalyst in the next isomerization reaction. Optionally, the product of the isomerization reaction can be distilled (fast xe2x80x9crush-overxe2x80x9d distillation) before the cyclization. Another option is a fractional distillation of the isomerization product in order to obtain fractions containing a higher concentration of ketone 4 before the cyclization. By-product fractions containing lower concentrations of ketone 4 can be reused (after optional redistillation) in the isomerization reaction.
Isolation and purification of ketone 1 from mixtures containing it in increased concentration, e.g., 12% and higher, is significantly easier than its isolation from mixtures containing less than 10%. It must be noted also that practically all concomitant materials obtained in the course of such purification processxe2x80x94mixtures containing mostly isomers 1, 3, 7, 8, 9xe2x80x94are themselves usable as aroma chemicals.
Thus, the invention provides a convenient environmentally benign and highly practical two-step process for obtaining ketone 1. The process provides higher yields of the target material as compared to the known methods.